Cardiovascular Diseases in Chronic Inflammatory Disorders

Introduction

Inflammation plays a crucial role in the process of atherogenesis.1 Cardiovascular disease (CVD) is a major cause of mortality and morbidity in patients with chronic inflammatory disorders, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), chronic human immunodeficiency virus (HIV) infection, and psoriasis.2,3 Patients with chronic inflammatory diseases have an increased risk of coronary heart disease (CHD), stroke, peripheral vascular disease (PVD), and cardiomyopathy that may not be fully captured by traditional CVD risk factors, such as dyslipidemia, aging, hypertension, and smoking.4

The established and earlier concept that passive deposition of lipids into arterial walls with subsequent covering of the deposits by smooth muscle and endothelial cells causes atherosclerosis has changed over the course of time.5 Contribution of the immune system to all phases of atherogenesis, including well-known inflammatory reactions consequent to intimal trapping and oxidation of low-density lipoprotein (LDL) cholesterol, have become increasingly evident.6 Besides atherosclerosis there has been a growing understanding of how chronic inflammation contributes to cardiomyopathy. Several randomized controlled trials have shown that an anti-inflammatory regimen may produce an improvement in left ventricular ejection fraction (LVEF) in certain subpopulations of idiopathic dilated cardiomyopathy patients.7-9 Therefore, targeting inflammatory pathways to curb the risk of CHD could prove to be a decisive preventive strategy. In this review, we summarize human inflammatory disease states that are associated with accelerated CHD.

Rheumatoid Arthritis and Cardiovascular Disease

RA is a chronic inflammatory disease of joints associated with increased mortality rates compared to the general population, with standardized mortality ratios between 1.3 and 2.3.10 Premature CVD is a contributor to the widened mortality gap observed between RA and non-RA population.11

Meta-analysis of 14 studies including 41,490 patients demonstrated a 48% increased risk of first ever cardiovascular events (CVE) in patients with RA compared to the general population. The risks for myocardial infarction (MI) and stroke were higher by 68% and 41% respectively.12 There was also a three-fold increase reported for carotid atherosclerosis in RA patients despite a more favorable risk factor profile.13 Notably, the increased incidence rates of CVEs in RA patients are independent of traditional CVD risk factors. Increased CV risk in RA patients is associated with accelerated atherosclerosis, endothelial dysfunction and changes in LV geometry. Due to these changes, combined circumferential and longitudinal LV systolic dysfunction is detectable in about one quarter of patients with asymptomatic RA despite preserved LVEF and is associated with LV concentric hypertrophy and remodeling.14

The immunopathology of RA is complicated, and it shares some common systemic inflammatory components with atherosclerosis. Large prospective cohort studies have shown benefit for anti-inflammatory therapies in reducing CVD risk in RA patients supporting the role of chronic inflammation in development of CHD in RA.15,16 Multiple animal studies have confirmed the atherogenic role of circulating activated immune cells and elevated inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-7) in RA.17,18 Targeting these cytokines may reduce not only the atherosclerotic burden, but also may reduce the inflammatory quality of the existing plaques.17

Psoriasis and Cardiovascular Disease

Psoriasis, one of the most common immune-mediated skin diseases, affects approximately 25 million people in North America and Europe. Despite increased prevalence of CVD risk factors, psoriasis is associated with increased vascular inflammation beyond cardiovascular risk factors.19-23 It also confers an independent risk for atherosclerosis, MI, stroke, and PVD.24-29 Psoriasis and atherosclerosis have common inflammatory pathways involving helper T cells type 1 (Th1) and 17 (Th17) that play an integral role in disease pathogenesis and progression. This may explain the increased risk of heart disease in psoriasis patients.30

Furthermore, psoriasis patients have increased risk of developing cardiomyopathy and heart failure (HF). A large cohort study demonstrated a significant dose-dependent relationship between psoriasis skin disease severity and new-onset clinical HF, with hazard ratios (HR) of 1.22 for mild and 1.53 for severe disease.31

A recent meta-analysis of seven observational studies including RA and psoriasis patients revealed that low dose methotrexate predicted a lower risk of CVEs and vascular inflammation.32 However, effect of methotrexate on vascular inflammation needs further exploration. Ongoing RCTs, such as the Vascular Inflammation in Psoriasis Trial (VIP), will test the impact of aggressive anti-inflammatory skin disease treatment on vascular disease in psoriasis.

Systemic Lupus Erythematosus and Cardiovascular Disease

SLE is an inflammatory autoimmune disease with a wide range of clinical manifestations and complications. Owing to improved and evolving clinical practice patterns over the last few decades, and the long-term survival of patients with SLE, CVD has become a leading cause of death.33 SLE patients have accelerated atherosclerosis that is not explained by traditional risk factors, and it is not limited to one vascular territory but actually overlaps between the coronary, carotid, and lower-extremity arteries.4,34 There is an increased risk of coronary artery disease (CAD), stroke, and peripheral arterial occlusive disease (PAOD) in SLE.4,35,36 A meta-analysis of 80 studies revealed increased carotid intima media thickness and carotid atherosclerosis in SLE patients compared to control population.37 Contrary to RA, SLE patients have subclinical LV deformation and impairment even with normal ejection fraction. In fact, there is a negative correlation between lupus activity and LV systolic strain.38

Multiple SLE-specific mechanisms such as auto-antibodies, raised inflammatory cytokine levels, endothelial cell dysfunction, vascular wall inflammation, and dyslipidemia also promote and accelerate atherosclerosis progression.29 Many SLE treatments reduce vascular inflammation and the risk of thrombo-occlusive events. Hydroxychloroquine, one of the common medications used to treat lupus, disrupts the production of IFNα, an inflammatory cytokine involved in endothelial cell dysfunction.40 Rituximab, a biological therapy, decreases inflammation by depleting B cells, and also results in improved lipid profile by reducing total cholesterol and triglycerides, and increasing high-density lipoprotein (HDL) cholesterol.41,42

Systemic Sclerosis and Cardiovascular Disease

SSc is a systemic autoimmune disease of unknown etiology associated with increased mortality, particularly due to cardiopulmonary complications.43 However, it is unclear whether accelerated atherosclerosis occurs in SSc. Studies designed to investigate the risk of subclinical atherosclerosis in scleroderma patients revealed equivocal findings.44 In a recent case-control study using carotid plaque as an outcome for atherosclerosis, SSc patients had 19.1% increase in subclinical atherosclerosis compared to 3% in healthy controls.45 Another large cohort study of 1239 SSc patients revealed a 13/1000 person-years incidence rate for myocardial infarction versus 4.1/1000 person-years in the comparison cohort with highest risk for MI within the first year of diagnosis.46 Additionally, SSc patients have impaired myocardial function, reduced RV contractility, RV diastolic dysfunction and alterations in LV contractility and diastolic function.47

Scleroderma vasculopathy can be explained by the vascular damage and endothelial cell activation due to increased vascular endothelial growth factor expression causing abnormal angiogenesis and circulating antibodies with anti-endothelial activity.48-50 However, larger studies investigating the mechanistic links between SSc and its vascular consequences are limited and should be carried out to further the knowledge in this aspect.

HIV and Cardiovascular Disease

An estimated 36.9 million people worldwide have HIV. In the past few years, as combination antiretroviral therapy availability has improved throughout the world, acquired immunodeficiency syndrome (AIDS) related deaths have also declined. HIV has transformed from a short-lived infection with high mortality to a virus-induced chronic disease with a chronic persistent inflammatory state characterized by persistent T-cell activation.

CVD has become one of the leading causes of non-AIDS-related morbidity and mortality.51 Patients with HIV have increased atherosclerotic CVD, predominantly subclinical atherosclerosis as shown by increased carotid intima-media thickness on ultrasound, greater risk of coronary artery atherosclerosis, and higher rates of subclinical myocardial inflammation on cardiac MRI.52-56 These measures serve as potential surrogates of increased CV morbidity and mortality observed in patients with chronic HIV infection. Moreover, HIV-associated cardiomyopathy is another known complication that can result from myocarditis, infiltration of myocardium with HIV virions, co-infection with other viruses (e.g., coxsackievirus B3, cytomegalovirus) or multifunctional inflammatory cytokine activation (such as TNF-a) by myocardial dendritic cells.57 Immune system deterioration affects CV outcomes in HIV patients. AIDS patients have increased in-hospital mortality due to acute myocardial infarction or stroke compared to HIV infected patients without AIDS.58

Conclusion

Accumulating evidence from epidemiology and human clinical research studies demonstrates that disease states known to harbor systemic inflammation elevate risk for CVD. Ongoing treatment trials of disease specific inflammation in RA, psoriasis, SLE, and HIV will inform whether curbing inflammation reduces CV morbidity and mortality. Furthermore, ongoing studies such as the Cardiovascular Inflammation Reduction Trial (CIRT) and the Cardiovascular Risk Reduction Study (CANTOS) will inform whether treatment of inflammation in those with known CVD (history of prior MI) will reduce future CV events. Regardless of the outcomes of these studies, knowledge of which pathways are involved in inflammatory atherogenesis will be augmented for future translational studies.

References

  1. Libby P, Ridker PM, Hansson GK, Leducq Transatlantic Network on Atherothrombosis. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 2009;54:2129-38.
  2. Ticani A, Rebaioli CB, Taglietti M, Shoenfeld Y. Heart involvement in systemic lupus erythematosus, anti-phospholipid syndrome and neonatal lupus. Rheumatology 2006;45:iv8-13.
  3. Teague H, Mehta NN. The link between inflammatory disorders and coronary heart disease: a look at recent studies and novel drugs in development. Curr Atheroscler Rep 2016;18:3.
  4. Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 2001;44:2331-7.
  5. Munro JM, Cotran RS. The pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Invest 1998;58:249-61.
  6. Lichtman AH, Binder CJ, Tsimikas S, Witztum JL. Adaptive immunity in atherogenesis: new insights and therapeutic approaches. J Clin Invest 2013;123:27-36.
  7. Parrillo JE. Inflammatory cardiomyopathy (myocarditis): which patients should be treated with anti-inflammatory therapy? Circulation 2001;104:4-6.
  8. Parrillo JE, Cunnion RE, Epstein SE, et al. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 1989;321:1061-8.
  9. Mason JW, O'Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 1995;333:269-75.
  10. Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994;37:481-94.
  11. Gonzalez A, Maradit Kremers H, Crowson CS, et al. The widening mortality gap between rheumatoid arthritis patients and the general population. Arthritis Rheum 2007;56:3583-7.
  12. Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 2012;71:1524-9.
  13. Roman MJ, Moeller E, Davis A, et al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med 2006;144:249-56.
  14. Cioffi G, Viapiana O, Ognibeni F, et al. Combined circumferential and longitudinal left ventricular systolic dysfunction in patients with rheumatoid arthritis without overt cardiac disease. J Am Soc Echocardiogr 2016;29:689-98.
  15. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173-7.
  16. Krishnan E, Lingala VB, Singh G. Declines in mortality from acute myocardial infarction in successive incidence and birth cohorts of patients with rheumatoid arthritis. Circulation 2004;110:1772-9.
  17. Ohta H, Wada H, Niwa T, et al. Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice. Atherosclerosis 2005;180:11-7.
  18. Devlin CM, Kuriakose G, Hirsch E, Tabas I. Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc Natl Acad Sci 2002;99:6280-5.
  19. Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies. Nutr Diabetes 2012;2:e54.
  20. Armstrong AW, Harskamp CT, Armstrong EJ. Psoriasis and the risk of diabetes mellitus: a systematic review and meta-analysis. JAMA Dermatol 2013;149:84-91.
  21. Azfar RS, Gelfand JM. Psoriasis and metabolic disease: epidemiology and pathophysiology. Curr Opin Rheumatol 2008;20:416-22.
  22. Langam SM, Seminara NM, Shin DB, et al. Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom. J Invest Dermatol 2012;132:556-62.
  23. Naik HB, Natarajan B, Stansky E, et al. Severity of psoriasis associates with aortic vascular inflammation detected by FDG PET/CT and neutrophil activation in a prospective observational study. Arterioscler Thromb Vasc Biol 2015;35:2667-76.
  24. Ahlehoff O, Gislason GH, Charlot M, et al. Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med 2011;270:147-57.
  25. Gelfand JM, Dommasch ED, Shin DB, et al. The risk of stroke in patients with psoriasis. J Invest Dermatol 2009;129:2411-8.
  26. Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J 2010;31:1000-6.
  27. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA 2006;296:1735-41.
  28. Kimball AB, Robinson D, Wu Y, et al. Cardiovascular disease and risk factors among psoriasis patients in two US healthcare databases, 2001-2002. Dermatology 2008;217:27-37.
  29. Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Ferdeman DG. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol 2009;145:700-3.
  30. Armstrong AW, Voyles SV, Armstrong EJ, Fuller EN, Rutledge JC. A tale of two plaques: convergent mechanisms of T-cell-mediated inflammation in psoriasis and atherosclerosis. Exp Dermatol 2011;20:544-9.
  31. Khalid U, Ahlehoff O, Gislason GH, et al. Psoriasis and risk of heart failure: a nationwide cohort study. Eur J Heart Fail 2014;16:743-8.
  32. De Vicchis R, Baldi C, Palmisani L. Protective effects of methotrexate against ischemic cardiovascular disorders in patients treated for rheumatoid arthritis or psoriasis: novel therapeutic insights coming from a meta-analysis of the literature data. Anatol J Cardiol 2016;16:2-9.
  33. Knight JS, Kaplan MJ. Cardiovascular disease in lupus: insights and updates. Curr Opin Rheumatol 2013;25:597-605.
  34. Kay SD, Poulsen MK, Diederichsen AC, Voss A. Coronary, carotid, and lower-extremity atherosclerosis and their interrelationship in Danish patients with systemic lupus erythematosus. J Rheumatol 2016;43:315-22.
  35. Chuang YW, Yu MC, Lin CL, Yu TM, Shu KH, Kao CH. Risk of peripheral arterial occlusive disease in patients with systemic lupus erythematosus: a nationwide population-based cohort study. Medicine 2015;94:e2121.
  36. Holmqvist M, Simard JF, Asplund K, Arkema EV. Stroke in systemic lupus erythematosus: a meta-analysis of population-based cohort studies. RMD Open 2015;1:e000168.
  37. Wu GC, Liu HR, Leng RX, et al. Subclinical atherosclerosis in patients with systemic lupus erythematosus: a systemic review and meta-analysis. Autoimmun Rev 2016;15:22-37.
  38. Leal GN, Silva KF, Lianza AC, et al. Subclinical left ventricular dysfunction in childhood-onset systemic lupus erythematosus: a two-dimensional speckle-tracking echocardiographic study. Scand J Rheumatol 2016;45:202-9.
  39. Skaggs BJ, Hahn BH, McMahon M. Accelerated atherosclerosis in patients with SLE—mechanisms and management. Nat Rev Rheumatol 2012;8:214-23.
  40. Sacre K, Criswell LA, McCune JM. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther 2012;14:R155.
  41. Jung H, Bobba R, Su J, et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 2010;62:863-8.
  42. Pego-Reigosa JM, Lu TY, Fontanillo MF, del Campo-Pérez V, Rahman A, Isenberg DA. Long-term improvement of lipid profile in patients with refractory systemic lupus erythematosus treated with B-cell depletion therapy: a retrospective observational study. Rheumatology 2010;49:691-6.
  43. Rubio-Rivas M, Royo C, Simeon CP, Corbella X, Fonollosa V. Mortality and survival in systemic sclerosis: systematic review and meta-analysis. Semin Arthritis Rheum 2014;44:208-19.
  44. Cannarile F, Valentini V, Mirabelli G, et al. Cardiovascular disease in systemic sclerosis. Ann Transl Med 2015;3:8.
  45. Ozen G, Inanc N, Unal AU, et al. Subclinical atherosclerosis in systemic sclerosis: not less frequent than rheumatoid arthritis and not detected with cardiovascular risk indices. Arthritis Care Res 2016. [Epub ahead of print]
  46. Aviña-Zubieta JA, Man A, Yurkovich M, Huang K, Sayre EC, Choi HK. Early cardiovascular disease after the diagnosis of systemic sclerosis. Am J Med 2016;129:324-31.
  47. Meune C, Khanna D, Aboulhosn J, et al. A right ventricular diastolic impairment is common in systemic sclerosis and is associated with other target-organ damage. Semin Arthritis Rheum 2016;45:439-45.
  48. Maurer B, Distler A, Suliman YA, et al. Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis. Ann Rheum Dis 2014;73:1880-7.
  49. Farouk HM, Hamza SH, El Bakry SA, et al. Dysregulation of angiogenic homeostasis in systemic sclerosis. Int J Rheum Dis 2013;16:448-54.
  50. Del Papa N, Quirici N, Scavullo C, et al. Antiendothelial cell antibodies induce apoptosis of bone marrow endothelial progenitors in systemic sclerosis. J Rheumatol 2010;37:2053-63.
  51. Miller CJ, Baker JV, Bormann AM, et al. Adjudicated morbidity and mortality outcomes by age among individuals with HIV infection on suppressive antiretroviral therapy. PLoS One 2014;9:e95061.
  52. Hulten E, Mitchell J, Scally J, Gibbs B, Villines TC. HIV positivity, protease inhibitor exposure and subclinical atherosclerosis: a systematic review and meta-analysis of observational studies. Heart 2009;95:1826-35.
  53. Lo J, Abbara S, Shturman L, et al. Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS 2010;24:243-53.
  54. Post WS, Budoff M, Kingsley L, et al. Associations between HIV infection and subclinical coronary atherosclerosis. Ann Intern Med 2014;160:458-67.
  55. Luetkens JA, Doerner J, Schwarze-Zander C, et al. Cardiac magnetic resonance reveals signs of subclinical myocardial inflammation in asymptomatic HIV-infected patients. Circ Cardiovasc Imaging 2016;9:e004091.
  56. Ntusi N, O'Dwyer E, Dorrell L, et al. HIV-1-related cardiovascular disease is associated with chronic inflammation, frequent pericardial effusions, and probable myocardial edema. Circ Cardiovasc Imaging 2016;9:e004430.
  57. Barbaro G. HIV-associated cardiomyopathy etiopathogenesis and clinical aspects. Herz 2005;30:486-92.
  58. Okeke NL, Hicks CB, McKellar MS, Fowler VG, Federspiel JJ. History of AIDS in HIV-infected patients is associated with higher in-hospital mortality following admission for acute myocardial infarction and stroke. J Infect Dis 2016;213:1955-61.

Clinical Topics: Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Vascular Medicine, Lipid Metabolism, Nonstatins, Acute Heart Failure, Echocardiography/Ultrasound, Hypertension

Keywords: Acquired Immunodeficiency Syndrome, Arthritis, Rheumatoid, Atherosclerosis, Autoimmune Diseases, B-Lymphocytes, Cardiomyopathy, Dilated, Carotid Artery Diseases, Carotid Intima-Media Thickness, Cholesterol, HDL, Cholesterol, LDL, Chronic Disease, Coronary Artery Disease, Dyslipidemias, Heart Failure, Hypertension, Myocardial Infarction, Lupus Erythematosus, Systemic, Myocarditis, Myocardium, Peripheral Vascular Diseases, Primary Prevention, Secondary Prevention, Risk Factors, Stroke, Stroke Volume, Vascular Endothelial Growth Factor A


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